EDITORIALS
Alterations of the Nasopharyngeal Microbiota in Infants with Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator and Antibiotic Effects Lung disease, characterized by chronic airway infection and inflammation, begins early in cystic fibrosis (CF). Bacterial pathogens (e.g., Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa) are frequently cultured from bronchoalveolar lavage fluid (BALF), and structural changes are demonstrable in infants and young children (1, 2). Using standard microbial culture, recognized CFassociated bacteria are detected routinely from CF airway samples (e.g., oropharyngeal [OP], expectorated and induced sputum, and BALF) (3). However, DNA-based sequencing approaches identify much more complex bacterial communities (or microbiota), including obligate anaerobic bacteria along with CF pathogens from these same samples (4). In adults and older children with CF, loss of bacterial community diversity in airway samples is associated with worse disease severity, chronic P. aeruginosa infection, and antibiotic use, suggesting microbiota analyses may serve as a useful biomarker of disease progression (5, 6). In people with CF who are unable to spontaneously expectorate sputum (typically young children), OP swabs are cultured routinely for bacterial surveillance, although correlation with lower airway cultures is not perfect for detection of CF pathogens (7). When analyzed using sequencing, the microbiota from OP swabs overlaps substantially with sputum, although CF pathogens may be underrepresented (8). In a study of seven infants with CF (three with early hospitalizations for prematurity and meconium ileus) followed longitudinally from age 1 to 21 months, a core microbiota dominated by Streptococcus, Prevotella, and Veillonella spp. was found in OP samples (9). Diversity increased during the first 2 years of life, and breastfeeding was associated with greater increases in diversity, suggesting a potential modifying effect. Nasopharyngeal (NP) sampling has been used in healthy infants to compare bacterial carriage rates and to examine the development of upper airway microbiota, using sequencing approaches (10–12). In healthy infants, NP microbiota community structure, particularly communities dominated by Haemophilus or Streptococcus spp., has been associated with an increased risk for lower respiratory tract infections, pneumonia, and the development of asthma (13). Although NP sampling has not been shown to improve detection of recognized pathogens in CF (14), changes in the microbiota may influence disease pathogenesis or serve as a marker of early susceptibility to disease progression. In this issue of the Journal, Prevaes and colleagues (pp. 504–515) report findings from a prospective, 6-month longitudinal study of NP microbiota development in 20 infants with CF and 45 healthy control infants (15). Infants were enrolled at the time of CF diagnosis with age-matched healthy controls; more than 70% of infants were enrolled before 1 month of age, and all were enrolled before age 3 months. NP swabs were collected monthly until 6 months of age and with acute respiratory symptoms. Swabs were analyzed using 16S rRNA–based sequencing, standard bacterial cultures, and viral polymerase chain reaction. A total of 324 NP swabs were collected, representing the most comprehensive examination of CF early NP microbiota to date. Even in the first few months of life, before first antibiotic exposure in all control infants and in 80% of infants with CF, the NP microbiota composition differed in CF compared with controls. When bacterial communities were clustered by the dominant
Editorials
bacteria, CF was more likely to be categorized as S. aureus dominated, whereas controls were more often categorized as Moraxella or Haemophilus dominated. Streptococcus emerged as a dominant bacterial species in CF and controls after 3 months, but was predominated by Streptococcus pneumoniae in healthy infants and Streptococcus mitis in infants with CF. The microbial community shifted significantly over the course of 6 months. Importantly, antibiotic use appeared to be associated with the most dramatic shifts in the microbiota, with alterations detectable after the first course of antibiotics. Antibiotic treatment was associated with a reduction in Moraxellaceae, Corynebacterium, and Dolosigranulum, and an increase in gramnegative bacteria, including Burkholderia. As Moraxellaceae, Corynebacterium, and Dolosigranulum have been associated with more stable NP microbiota and decreased risk for respiratory diseases in healthy infants (13), reductions in these taxa may be detrimental. Although the authors state that their practice is not to use chronic antibiotics routinely unless infants are symptomatic, 70% of the infants with CF in this study were treated with chronic antibiotics by age 6 months, demonstrating the problem of early respiratory symptoms and frequent antibiotic use in this population. It is possible that the use of antibiotics is having the unintended consequence of lowering the abundance of healthy commensal bacteria in the upper airway, allowing expansion of potentially pathogenic bacteria. Interestingly, shifts in diversity were not seen over time, perhaps because of the relatively short follow-up of 6 months or sample type. Diversity and community composition also did not shift before or after respiratory infections. Breastfeeding was associated with increased Moraxellaceae and Corynebacterium and lower abundance of Prevotella, Haemophilus, Porphyromonas, and Actinomyces spp., further supporting that breastfeeding may play an important role in early microbiota development. In this study, the authors observed potential microbial interference networks with clusters of bacteria co-occurring, such as Streptococcus and Burkholderia spp., as well as clusters with strong negative interactions including Corynebacterium and Moraxella clusters and H. influenzae and between the Corynebacterium cluster and S. aureus. Understanding interactions between bacterial species in health and disease may provide opportunities in the future for clinical intervention. Although this represents the most comprehensive examination to date of early infant microbiota in CF, the study was still limited by relatively small size, short follow-up time, and lack of geographic diversity. Respiratory infections were diagnosed by report and likely varied in severity. Changes in the NP microbiota have been shown to occur seasonally (16); the small numbers in this study precluded examining time of year as a factor. There were also differences in characteristics between healthy control infants and infants with CF, including day care attendance, number of siblings, and length of breastfeeding, that may have contributed to the alterations in microbiota, although differences seen before 3 months of age are likely less affected by these factors. The NP microbiota described in this study varied somewhat from other studies of the CF upper airway, possibly because of the differences in NP versus OP
473
EDITORIALS communities. In the study by Madan and colleagues, Moraxella and Corynebacterium spp. were found only in low relative abundance, whereas Streptococcus spp. was present in higher relative abundance (9). In conclusion, this longitudinal study indicates that infants with CF acquire a distinct nasopharyngeal microbiota, even before intervention with antimicrobials, compared with healthy infants, suggesting that innate differences in the host (e.g., CF transmembrane conductance regulator dysfunction) drive some of these early alterations. Antibiotics are used early and frequently in CF, and may have the unintended consequence of shifting the microbiota toward a less “healthy” structure. Chronic S. aureus prophylactic treatment for this age group continues to be debated, and future investigations of this approach should include microbiota analyses (17). The relationship between upper airway microbiota and development of lower respiratory tract infection, inflammation, and structural lung disease in CF is not yet clear and will need further study, as do alternative approaches such as probiotics, encouraging longer breastfeeding, or more judicious use of antimicrobials. n Author disclosures are available with the text of this article at www.atsjournals.org. Edith T. Zemanick, M.D., M.S.C.S. Department of Pediatrics University of Colorado School of Medicine Aurora, Colorado Claire Wainwright, M.B.B.S., M.D. Department of Respiratory and Sleep Medicine Lady Cilento Children’s Hospital South Brisbane, Queensland, Australia and School of Medicine University of Queensland Brisbane, Queensland, Australia
ORCID IDs: 0000-0002-7507-9337 (E.T.Z.); 0000-0001-8389-3809 (C.W.).
References 1. Sly PD, Gangell CL, Chen L, Ware RS, Ranganathan S, Mott LS, Murray CP, Stick SM; AREST CF Investigators. Risk factors for bronchiectasis in children with cystic fibrosis. N Engl J Med 2013;368:1963–1970. 2. Stick SM, Brennan S, Murray C, Douglas T, von Ungern-Sternberg BS, Garratt LW, Gangell CL, De Klerk N, Linnane B, Ranganathan S, et al.; Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF). Bronchiectasis in infants and preschool children diagnosed with cystic fibrosis after newborn screening. J Pediatr 2009;155:623–628.e1. 3. Razvi S, Quittell L, Sewall A, Quinton H, Marshall B, Saiman L. Respiratory microbiology of patients with cystic fibrosis in the United States, 1995 to 2005. Chest 2009;136:1554–1560.
4. Caverly LJ, Zhao J, LiPuma JJ. Cystic fibrosis lung microbiome: opportunities to reconsider management of airway infection. Pediatr Pulmonol 2015;50:S31–S38. 5. Zhao J, Schloss PD, Kalikin LM, Carmody LA, Foster BK, Petrosino JF, Cavalcoli JD, VanDevanter DR, Murray S, Li JZ, et al. Decade-long bacterial community dynamics in cystic fibrosis airways. Proc Natl Acad Sci USA 2012;109:5809–5814. 6. Stressmann FA, Rogers GB, van der Gast CJ, Marsh P, Vermeer LS, Carroll MP, Hoffman L, Daniels TW, Patel N, Forbes B, et al. Long-term cultivation-independent microbial diversity analysis demonstrates that bacterial communities infecting the adult cystic fibrosis lung show stability and resilience. Thorax 2012;67:867–873. 7. Rosenfeld M, Emerson J, Accurso F, Armstrong D, Castile R, Grimwood K, Hiatt P, McCoy K, McNamara S, Ramsey B, et al. Diagnostic accuracy of oropharyngeal cultures in infants and young children with cystic fibrosis. Pediatr Pulmonol 1999;28:321–328. 8. Zemanick ET, Wagner BD, Robertson CE, Stevens MJ, Szefler SJ, Accurso FJ, Sagel SD, Harris JK. Assessment of airway microbiota and inflammation in cystic fibrosis using multiple sampling methods. Ann Am Thorac Soc 2015;12:221–229. 9. Madan JC, Koestler DC, Stanton BA, Davidson L, Moulton LA, Housman ML, Moore JH, Guill MF, Morrison HG, Sogin ML, et al. Serial analysis of the gut and respiratory microbiome in cystic fibrosis in infancy: interaction between intestinal and respiratory tracts and impact of nutritional exposures. MBio 2012;3:3. 10. Biesbroek G, Bosch AA, Wang X, Keijser BJ, Veenhoven RH, Sanders EA, Bogaert D. The impact of breastfeeding on nasopharyngeal microbial communities in infants. Am J Respir Crit Care Med 2014;190:298–308. 11. Faden H. Monthly prevalence of group A, B and G Streptococcus, Haemophilus influenzae types E and F and Pseudomonas aeruginosa nasopharyngeal colonization in the first two years of life. Pediatr Infect Dis J 1998;17:255–256. 12. Velazquez-Guadarrama ´ N, Martinez-Aguilar G, Galindo JA, Zuñiga G, Arbo-Sosa A. Methicillin-resistant S. aureus colonization in Mexican children attending day care centres. Clin Invest Med 2009;32:E57–E63. 13. Teo SM, Mok D, Pham K, Kusel M, Serralha M, Troy N, Holt BJ, Hales BJ, Walker ML, Hollams E, et al. The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development. Cell Host Microbe 2015;17:704–715. 14. Taylor L, Corey M, Matlow A, Sweezey NB, Ratjen F. Comparison of throat swabs and nasopharyngeal suction specimens in non-sputum-producing patients with cystic fibrosis. Pediatr Pulmonol 2006;41:839–843. 15. Prevaes SM, de Winter-de Groot KM, Janssens HM, de Steenhuijsen Piters WA, Tramper-Stranders GA, Wyllie AL, Hasrat R, Tiddens HA, van Westreenen M, van der Ent CK, et al. Development of the nasopharyngeal microbiota in infants with cystic fibrosis. Am J Respir Crit Care Med 2016;193:504–515. 16. Bogaert D, Keijser B, Huse S, Rossen J, Veenhoven R, van Gils E, Bruin J, Montijn R, Bonten M, Sanders E. Variability and diversity of nasopharyngeal microbiota in children: a metagenomic analysis. PLoS One 2011;6:e17035. 17. Smyth A. Prophylactic antibiotics in cystic fibrosis: a conviction without evidence? Pediatr Pulmonol 2005;40:471–476.
Copyright © 2016 by the American Thoracic Society
Bridge or Abyss: Extracorporeal Membrane Oxygenation for Acute Respiratory Failure in Interstitial Lung Disease Interstitial lung disease (ILD) defines an entity or a syndrome of chronic alterations of lung parenchyma characterized by inflammation and/or fibrosis (1, 2). ILD can be induced by defined conditions such as pneumonia or fibrosis. It can be classified as 474
idiopathic if a predisposing factor cannot be identified or if the underlying pathophysiology is not totally understood. A multidisciplinary approach allows a definitive diagnosis, and reasonable progress with respect to pharmacological treatment
American Journal of Respiratory and Critical Care Medicine Volume 193 Number 5 | March 1 2016
Alterations of the Nasopharyngeal Microbiota in Infants with Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator and Antibiotic Effects Lung disease, characterized by chronic airway infection and inflammation, begins early in cystic fibrosis (CF). Bacterial pathogens (e.g., Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa) are frequently cultured from bronchoalveolar lavage fluid (BALF), and structural changes are demonstrable in infants and young children (1, 2). Using standard microbial culture, recognized CFassociated bacteria are detected routinely from CF airway samples (e.g., oropharyngeal [OP], expectorated and induced sputum, and BALF) (3). However, DNA-based sequencing approaches identify much more complex bacterial communities (or microbiota), including obligate anaerobic bacteria along with CF pathogens from these same samples (4). In adults and older children with CF, loss of bacterial community diversity in airway samples is associated with worse disease severity, chronic P. aeruginosa infection, and antibiotic use, suggesting microbiota analyses may serve as a useful biomarker of disease progression (5, 6). In people with CF who are unable to spontaneously expectorate sputum (typically young children), OP swabs are cultured routinely for bacterial surveillance, although correlation with lower airway cultures is not perfect for detection of CF pathogens (7). When analyzed using sequencing, the microbiota from OP swabs overlaps substantially with sputum, although CF pathogens may be underrepresented (8). In a study of seven infants with CF (three with early hospitalizations for prematurity and meconium ileus) followed longitudinally from age 1 to 21 months, a core microbiota dominated by Streptococcus, Prevotella, and Veillonella spp. was found in OP samples (9). Diversity increased during the first 2 years of life, and breastfeeding was associated with greater increases in diversity, suggesting a potential modifying effect. Nasopharyngeal (NP) sampling has been used in healthy infants to compare bacterial carriage rates and to examine the development of upper airway microbiota, using sequencing approaches (10–12). In healthy infants, NP microbiota community structure, particularly communities dominated by Haemophilus or Streptococcus spp., has been associated with an increased risk for lower respiratory tract infections, pneumonia, and the development of asthma (13). Although NP sampling has not been shown to improve detection of recognized pathogens in CF (14), changes in the microbiota may influence disease pathogenesis or serve as a marker of early susceptibility to disease progression. In this issue of the Journal, Prevaes and colleagues (pp. 504–515) report findings from a prospective, 6-month longitudinal study of NP microbiota development in 20 infants with CF and 45 healthy control infants (15). Infants were enrolled at the time of CF diagnosis with age-matched healthy controls; more than 70% of infants were enrolled before 1 month of age, and all were enrolled before age 3 months. NP swabs were collected monthly until 6 months of age and with acute respiratory symptoms. Swabs were analyzed using 16S rRNA–based sequencing, standard bacterial cultures, and viral polymerase chain reaction. A total of 324 NP swabs were collected, representing the most comprehensive examination of CF early NP microbiota to date. Even in the first few months of life, before first antibiotic exposure in all control infants and in 80% of infants with CF, the NP microbiota composition differed in CF compared with controls. When bacterial communities were clustered by the dominant
Editorials
bacteria, CF was more likely to be categorized as S. aureus dominated, whereas controls were more often categorized as Moraxella or Haemophilus dominated. Streptococcus emerged as a dominant bacterial species in CF and controls after 3 months, but was predominated by Streptococcus pneumoniae in healthy infants and Streptococcus mitis in infants with CF. The microbial community shifted significantly over the course of 6 months. Importantly, antibiotic use appeared to be associated with the most dramatic shifts in the microbiota, with alterations detectable after the first course of antibiotics. Antibiotic treatment was associated with a reduction in Moraxellaceae, Corynebacterium, and Dolosigranulum, and an increase in gramnegative bacteria, including Burkholderia. As Moraxellaceae, Corynebacterium, and Dolosigranulum have been associated with more stable NP microbiota and decreased risk for respiratory diseases in healthy infants (13), reductions in these taxa may be detrimental. Although the authors state that their practice is not to use chronic antibiotics routinely unless infants are symptomatic, 70% of the infants with CF in this study were treated with chronic antibiotics by age 6 months, demonstrating the problem of early respiratory symptoms and frequent antibiotic use in this population. It is possible that the use of antibiotics is having the unintended consequence of lowering the abundance of healthy commensal bacteria in the upper airway, allowing expansion of potentially pathogenic bacteria. Interestingly, shifts in diversity were not seen over time, perhaps because of the relatively short follow-up of 6 months or sample type. Diversity and community composition also did not shift before or after respiratory infections. Breastfeeding was associated with increased Moraxellaceae and Corynebacterium and lower abundance of Prevotella, Haemophilus, Porphyromonas, and Actinomyces spp., further supporting that breastfeeding may play an important role in early microbiota development. In this study, the authors observed potential microbial interference networks with clusters of bacteria co-occurring, such as Streptococcus and Burkholderia spp., as well as clusters with strong negative interactions including Corynebacterium and Moraxella clusters and H. influenzae and between the Corynebacterium cluster and S. aureus. Understanding interactions between bacterial species in health and disease may provide opportunities in the future for clinical intervention. Although this represents the most comprehensive examination to date of early infant microbiota in CF, the study was still limited by relatively small size, short follow-up time, and lack of geographic diversity. Respiratory infections were diagnosed by report and likely varied in severity. Changes in the NP microbiota have been shown to occur seasonally (16); the small numbers in this study precluded examining time of year as a factor. There were also differences in characteristics between healthy control infants and infants with CF, including day care attendance, number of siblings, and length of breastfeeding, that may have contributed to the alterations in microbiota, although differences seen before 3 months of age are likely less affected by these factors. The NP microbiota described in this study varied somewhat from other studies of the CF upper airway, possibly because of the differences in NP versus OP
473
EDITORIALS communities. In the study by Madan and colleagues, Moraxella and Corynebacterium spp. were found only in low relative abundance, whereas Streptococcus spp. was present in higher relative abundance (9). In conclusion, this longitudinal study indicates that infants with CF acquire a distinct nasopharyngeal microbiota, even before intervention with antimicrobials, compared with healthy infants, suggesting that innate differences in the host (e.g., CF transmembrane conductance regulator dysfunction) drive some of these early alterations. Antibiotics are used early and frequently in CF, and may have the unintended consequence of shifting the microbiota toward a less “healthy” structure. Chronic S. aureus prophylactic treatment for this age group continues to be debated, and future investigations of this approach should include microbiota analyses (17). The relationship between upper airway microbiota and development of lower respiratory tract infection, inflammation, and structural lung disease in CF is not yet clear and will need further study, as do alternative approaches such as probiotics, encouraging longer breastfeeding, or more judicious use of antimicrobials. n Author disclosures are available with the text of this article at www.atsjournals.org. Edith T. Zemanick, M.D., M.S.C.S. Department of Pediatrics University of Colorado School of Medicine Aurora, Colorado Claire Wainwright, M.B.B.S., M.D. Department of Respiratory and Sleep Medicine Lady Cilento Children’s Hospital South Brisbane, Queensland, Australia and School of Medicine University of Queensland Brisbane, Queensland, Australia
ORCID IDs: 0000-0002-7507-9337 (E.T.Z.); 0000-0001-8389-3809 (C.W.).
References 1. Sly PD, Gangell CL, Chen L, Ware RS, Ranganathan S, Mott LS, Murray CP, Stick SM; AREST CF Investigators. Risk factors for bronchiectasis in children with cystic fibrosis. N Engl J Med 2013;368:1963–1970. 2. Stick SM, Brennan S, Murray C, Douglas T, von Ungern-Sternberg BS, Garratt LW, Gangell CL, De Klerk N, Linnane B, Ranganathan S, et al.; Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF). Bronchiectasis in infants and preschool children diagnosed with cystic fibrosis after newborn screening. J Pediatr 2009;155:623–628.e1. 3. Razvi S, Quittell L, Sewall A, Quinton H, Marshall B, Saiman L. Respiratory microbiology of patients with cystic fibrosis in the United States, 1995 to 2005. Chest 2009;136:1554–1560.
4. Caverly LJ, Zhao J, LiPuma JJ. Cystic fibrosis lung microbiome: opportunities to reconsider management of airway infection. Pediatr Pulmonol 2015;50:S31–S38. 5. Zhao J, Schloss PD, Kalikin LM, Carmody LA, Foster BK, Petrosino JF, Cavalcoli JD, VanDevanter DR, Murray S, Li JZ, et al. Decade-long bacterial community dynamics in cystic fibrosis airways. Proc Natl Acad Sci USA 2012;109:5809–5814. 6. Stressmann FA, Rogers GB, van der Gast CJ, Marsh P, Vermeer LS, Carroll MP, Hoffman L, Daniels TW, Patel N, Forbes B, et al. Long-term cultivation-independent microbial diversity analysis demonstrates that bacterial communities infecting the adult cystic fibrosis lung show stability and resilience. Thorax 2012;67:867–873. 7. Rosenfeld M, Emerson J, Accurso F, Armstrong D, Castile R, Grimwood K, Hiatt P, McCoy K, McNamara S, Ramsey B, et al. Diagnostic accuracy of oropharyngeal cultures in infants and young children with cystic fibrosis. Pediatr Pulmonol 1999;28:321–328. 8. Zemanick ET, Wagner BD, Robertson CE, Stevens MJ, Szefler SJ, Accurso FJ, Sagel SD, Harris JK. Assessment of airway microbiota and inflammation in cystic fibrosis using multiple sampling methods. Ann Am Thorac Soc 2015;12:221–229. 9. Madan JC, Koestler DC, Stanton BA, Davidson L, Moulton LA, Housman ML, Moore JH, Guill MF, Morrison HG, Sogin ML, et al. Serial analysis of the gut and respiratory microbiome in cystic fibrosis in infancy: interaction between intestinal and respiratory tracts and impact of nutritional exposures. MBio 2012;3:3. 10. Biesbroek G, Bosch AA, Wang X, Keijser BJ, Veenhoven RH, Sanders EA, Bogaert D. The impact of breastfeeding on nasopharyngeal microbial communities in infants. Am J Respir Crit Care Med 2014;190:298–308. 11. Faden H. Monthly prevalence of group A, B and G Streptococcus, Haemophilus influenzae types E and F and Pseudomonas aeruginosa nasopharyngeal colonization in the first two years of life. Pediatr Infect Dis J 1998;17:255–256. 12. Velazquez-Guadarrama ´ N, Martinez-Aguilar G, Galindo JA, Zuñiga G, Arbo-Sosa A. Methicillin-resistant S. aureus colonization in Mexican children attending day care centres. Clin Invest Med 2009;32:E57–E63. 13. Teo SM, Mok D, Pham K, Kusel M, Serralha M, Troy N, Holt BJ, Hales BJ, Walker ML, Hollams E, et al. The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development. Cell Host Microbe 2015;17:704–715. 14. Taylor L, Corey M, Matlow A, Sweezey NB, Ratjen F. Comparison of throat swabs and nasopharyngeal suction specimens in non-sputum-producing patients with cystic fibrosis. Pediatr Pulmonol 2006;41:839–843. 15. Prevaes SM, de Winter-de Groot KM, Janssens HM, de Steenhuijsen Piters WA, Tramper-Stranders GA, Wyllie AL, Hasrat R, Tiddens HA, van Westreenen M, van der Ent CK, et al. Development of the nasopharyngeal microbiota in infants with cystic fibrosis. Am J Respir Crit Care Med 2016;193:504–515. 16. Bogaert D, Keijser B, Huse S, Rossen J, Veenhoven R, van Gils E, Bruin J, Montijn R, Bonten M, Sanders E. Variability and diversity of nasopharyngeal microbiota in children: a metagenomic analysis. PLoS One 2011;6:e17035. 17. Smyth A. Prophylactic antibiotics in cystic fibrosis: a conviction without evidence? Pediatr Pulmonol 2005;40:471–476.
Copyright © 2016 by the American Thoracic Society
Bridge or Abyss: Extracorporeal Membrane Oxygenation for Acute Respiratory Failure in Interstitial Lung Disease Interstitial lung disease (ILD) defines an entity or a syndrome of chronic alterations of lung parenchyma characterized by inflammation and/or fibrosis (1, 2). ILD can be induced by defined conditions such as pneumonia or fibrosis. It can be classified as 474
idiopathic if a predisposing factor cannot be identified or if the underlying pathophysiology is not totally understood. A multidisciplinary approach allows a definitive diagnosis, and reasonable progress with respect to pharmacological treatment
American Journal of Respiratory and Critical Care Medicine Volume 193 Number 5 | March 1 2016
