Early origins of lung disease: Towards an interdisciplinary approach

The prenatal and perinatal environments can have profound effects on the development of chronic inflammatory diseases. However, mechanistic insight into how the early-life microenvironment can impact upon development of the lung and immune system and consequent initiation and progression of respiratory diseases is still emerging. Recent studies investigating the developmental origins of lung diseases have started to delineate the effects of early-life changes in the lung, environmental exposures and immune maturation on the development of childhood and adult lung diseases. While the influencing factors have been described and studied in mostly animal models, it remains challenging to pinpoint exactly which factors and at which time point are detrimental in lung development leading to respiratory disease later in life. To advance our understanding of early origins of chronic lung disease and to allow for proper dissemination and application of this knowledge, we propose four major focus areas: 1) policy and education; 2) clinical assessment; 3) basic and translational research; and 4) infrastructure and tools, and discuss future directions for advancement. This review is a follow-up of the discussions at the European Respiratory Society Research Seminar “Early origins of lung disease: towards an interdisciplinary approach” (Lisbon, Portugal, November 2019)

Respiratory tract microbiota: gatekeeper to respiratory health

Respiratory tract infections (RTIs), such as pneumonia, are responsible for a large burden of disease, with the highest incidence and mortality in young children and elderly adults. Yearly, approximately 900,000 children die because of pneumonia globally, making up for ~15% of all deaths in children under the age of 5 years worldwide. Respiratory tract infections are also a major reason for (inappropriate) antibiotic prescriptions, which further underscores the relevance of RTIs. These infections have long been considered in isolation and viewed within the Koch’s one-host one-pathogen paradigm. However, the human body is colonized by vast numbers of specialised bacterial communities, conjointly referred to as the bacterial microbiome. The advent of next-generation sequencing techniques enabled us to characterise the entirety of the microbial community (microbiota) and its functional capacity (microbiome). Among others, the microbiome appears involved in steering immune development, setting an individual on a trajectory towards or away from disease. In addition, diverse resident bacterial communities provide us with ‘colonization resistance’, therewith protecting the human host from incoming or blooming pathogens. In this thesis, we study the role of the (upper) respiratory tract microbiota in health and in respiratory disease. In chapter 3, we characterise the healthy respiratory tract microbiota development in a cohort of healthy, unselected children over the first year of life. We demonstrate that microbiota changes within the first month of life are associated with long term susceptibility to respiratory infections. In chapter 4 and chapter 5 we study dynamics of nasal carriage of Streptococcus pneumoniae, in the context of the live-attenuated influenza vaccine. S. pneumoniae is a commensal with pathogenic potential, being able to cause severe lower RTIs, including pneumonia. Using an experimental human challenge model, we found that vaccination prior to pneumococcal inoculation increases pneumococcal carriage rate and density. Furthermore we found that the nasal microbiota present before pneumococcal challenge/vaccination determined pneumococcal receptiveness. We identified a new host phenotype of low-dense pneumococcal carriers, who seem to be able to control pneumococcal carriage well, resulting in the least microbial perturbations over time. In chapter 7 we studied the oropharyngeal microbiota in pneumonia and healthy adults and elderly, showing that particularly the absence of a group of harmless commensals is associated with pneumonia, more than the presence of pathogens. In chapter 8 we characterise the nasopharyngeal microbiota and host immune response in healthy children and children with a mild or severe infection with respiratory syncytial virus (RSV). Our data suggested that interactions between RSV and nasopharyngeal microbiota might modulate the host immune response, potentially impacting disease severity. Combined, these studies demonstrated the likely role of respiratory microbial communities in carriage of pathogens and susceptibility to RTIs. Furthermore, we also found differences in microbial communities during RTI that might drive inflammation and thereby severity of disease. Further studies are needed to further unravel cause-effect relationships in more detail, however we believe the studies presented in this thesis underline the importance of the respiratory tract microbiota as gatekeeper to respiratory health

Respiratory tract microbiota: gatekeeper to respiratory health

Respiratory tract infections (RTIs), such as pneumonia, are responsible for a large burden of disease, with the highest incidence and mortality in young children and elderly adults. Yearly, approximately 900,000 children die because of pneumonia globally, making up for ~15% of all deaths in children under the age of 5 years worldwide. Respiratory tract infections are also a major reason for (inappropriate) antibiotic prescriptions, which further underscores the relevance of RTIs. These infections have long been considered in isolation and viewed within the Koch’s one-host one-pathogen paradigm. However, the human body is colonized by vast numbers of specialised bacterial communities, conjointly referred to as the bacterial microbiome. The advent of next-generation sequencing techniques enabled us to characterise the entirety of the microbial community (microbiota) and its functional capacity (microbiome). Among others, the microbiome appears involved in steering immune development, setting an individual on a trajectory towards or away from disease. In addition, diverse resident bacterial communities provide us with ‘colonization resistance’, therewith protecting the human host from incoming or blooming pathogens. In this thesis, we study the role of the (upper) respiratory tract microbiota in health and in respiratory disease. In chapter 3, we characterise the healthy respiratory tract microbiota development in a cohort of healthy, unselected children over the first year of life. We demonstrate that microbiota changes within the first month of life are associated with long term susceptibility to respiratory infections. In chapter 4 and chapter 5 we study dynamics of nasal carriage of Streptococcus pneumoniae, in the context of the live-attenuated influenza vaccine. S. pneumoniae is a commensal with pathogenic potential, being able to cause severe lower RTIs, including pneumonia. Using an experimental human challenge model, we found that vaccination prior to pneumococcal inoculation increases pneumococcal carriage rate and density. Furthermore we found that the nasal microbiota present before pneumococcal challenge/vaccination determined pneumococcal receptiveness. We identified a new host phenotype of low-dense pneumococcal carriers, who seem to be able to control pneumococcal carriage well, resulting in the least microbial perturbations over time. In chapter 7 we studied the oropharyngeal microbiota in pneumonia and healthy adults and elderly, showing that particularly the absence of a group of harmless commensals is associated with pneumonia, more than the presence of pathogens. In chapter 8 we characterise the nasopharyngeal microbiota and host immune response in healthy children and children with a mild or severe infection with respiratory syncytial virus (RSV). Our data suggested that interactions between RSV and nasopharyngeal microbiota might modulate the host immune response, potentially impacting disease severity. Combined, these studies demonstrated the likely role of respiratory microbial communities in carriage of pathogens and susceptibility to RTIs. Furthermore, we also found differences in microbial communities during RTI that might drive inflammation and thereby severity of disease. Further studies are needed to further unravel cause-effect relationships in more detail, however we believe the studies presented in this thesis underline the importance of the respiratory tract microbiota as gatekeeper to respiratory health

Increased risk of pneumonia in residents living near poultry farms: does the upper respiratory tract microbiota play a role?

Background Air pollution has been shown to increase the susceptibility to community-acquired pneumonia (CAP). Previously, we observed an increased incidence of CAP in adults living within 1 km from poultry farms, potentially related to particulate matter and endotoxin emissions. We aim to confirm the increased risk of CAP near poultry farms by refined spatial analyses, and we hypothesize that the oropharyngeal microbiota composition in CAP patients may be associated with residential proximity to poultry farms. Methods A spatial kernel model was used to analyze the association between proximity to poultry farms and CAP diagnosis, obtained from electronic medical records of 92,548 GP patients. The oropharyngeal microbiota composition was determined in 126 hospitalized CAP patients using 16S-rRNA-based sequencing, and analyzed in relation to residential proximity to poultry farms. Results Kernel analysis confirmed a significantly increased risk of CAP when living near poultry farms, suggesting an excess risk up to 1.15 km, followed by a sharp decline. Overall, the oropharyngeal microbiota composition differed borderline significantly between patients living <1 km and ≥1 km from poultry farms (PERMANOVA p = 0.075). Results suggested a higher abundance of Streptococcus pneumoniae (mean relative abundance 34.9% vs. 22.5%, p = 0.058) in patients living near poultry farms, which was verified by unsupervised clustering analysis, showing overrepresentation of a S. pneumoniae cluster near poultry farms (p = 0.049). Conclusion Living near poultry farms is associated with an 11% increased risk of CAP, possibly resulting from changes in the upper respiratory tract microbiota composition in susceptible individuals. The abundance of S. pneumoniae near farms needs to be replicated in larger, independent studies