New Opportunities for Managing Acute and Chronic Lung Infections

New Opportunities for Managing Acute and Chronic Lung Infections

PERSPECTIVES and their potential interactions with each OPINION other and airway commensals. We discuss the emergence of antibiotic multidrug- New opportunities for managing resistant (MDR) organisms and highlight the potential for the global spread of pathogens through circulation in cities, schools and acute and chronic lung infections hospitals. We then suggest novel diagnostic and therapeutic possibilities for mitigating William O. C. M. Cookson, Michael J. Cox and Miriam F. Moffatt these serious problems. We propose that Abstract | Lung diseases caused by microbial infections affect hundreds of millions the opportunities to improve patient care are substantial and that a coordinated and of children and adults throughout the world. In Western populations, the treatment of collaborative international Lung Microbiome lung infections is a primary driver of antibiotic resistance. Traditional therapeutic Project (to consider the collective genomes strategies have been based on the premise that the healthy lung is sterile and that of the microorganisms that reside in the infections grow in a pristine environment. As a consequence, rapid advances in our lung) together with systematic studies of understanding of the composition of the microbiota of the skin and bowel have not individual organisms (the microbiota) will be of inestimable value to global health. yet been matched by studies of the respiratory tree. The recognition that the lungs are as populated with microorganisms as other mucosal surfaces provides the The burden of lung infections opportunity to reconsider the mechanisms and management of lung infections. Overt respiratory infections are the leading Molecular analyses of the lung microbiota are revealing profound adverse responses cause of death in developing countries and to widespread antibiotic use, urbanization and globalization. This Opinion article are associated with more than 4 million 16 proposes how technologies and concepts flowing from the Human Microbiome deaths annually . In children under 5 years of age, pneumonia, which is usually Project can transform the diagnosis and treatment of common lung diseases. associated with a bacterial infection, accounts for 1.3 million deaths annually The airways and the lung are in a constant Until recently, standard medical teaching and 18% of all-cause mortality17. Moreover, state of challenge from environmental held that the healthy lung is sterile9 and that pneumonia kills far more adults than HIV microorganisms. A sedentary adult can pathogens invade an environment that is or malaria16. Globally, lower respiratory inhale more than 10,000 litres of air per normally kept free of microorganisms by the infections result in the loss of 103,000 day1, which washes over 40–80 m2 of lung host mucosa. However, the thoracic airways, disability-adjusted life years, which means surface2,3. In cities, this air may contain up which are the site of many infections, that lung infections are the largest cause of to 100,000 bacteria per litre4, a proportion are now known to support a distinctive disease burden to humanity. of which are able to penetrate into the community with a density of bacteria Acute infections can afflict healthy thoracic airways and beyond. By contrast, similar to that of the small bowel10,11. The adults but are more common in the the gut has a surface area of 30 m2 (REF. 5), consideration of how diverse commensal very young or very old or in those with and microbial ingression is limited by microbial communities resist exogenous underlying health problems. They usually gastric acid. Thus, it is not surprising that infection12–14 has had an enormous influence affect the lung parenchyma (pneumonia), lung infections commonly affect human on understanding and treating bowel the airways of the lung (bronchitis) or health. In the United Kingdom alone, diseases15, and it is timely now to reconsider both (bronchopneumonia) (FIG. 1). Less 16 million patients of the National Health received wisdom for the management of frequently, infections can spread to the Service are treated with antibiotics each year lung infections. Accessing the lower airways linings of the lung, causing pleurisy and for respiratory tract infections that include for routine microbial analyses typically empyema. CAP differs from hospital- 260,000 episodes of community-acquired involves invasive procedures such as acquired pneumonia (HAP) and pneumonia (CAP)6. Antibiotic prescription fibre-optic bronchoscopy. These practical ventilator-associated pneumonia (VAP), rates are higher in many other European difficulties, and the low priority given which occur in patients who are sick or countries than in the United Kingdom7. to non-HIV lung disease by the Human immunocompromised and result in high In the United States, acute lung infection Microbiome Project (HMP), mean that the morbidity, mortality and costs18. in the presence of underlying chronic technological and analytical advances of In contrast to acute infections, chronic obstructive pulmonary disease (COPD) is the HMP have been sparsely applied to the lung infections are typically a consequence the most common reason for administering airways and the lung. of underlying disease. For example, antimicrobial therapy to adults; this clinical In this Opinion article, we review the bronchiectasis describes dilations in the setting plays a substantial role in driving most common pulmonary infective agents, thoracic airways (FIG. 1), which can be antimicrobial resistance8. with an emphasis on bacterial pathogens caused by tuberculosis, scarring after NATURE REVIEWS | MICROBIOLOGY VOLUME 16 | FEBRUARY 2018 | 111 ©2017 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved. PERSPECTIVES Tuberculosis Lobar pneumonia inflammation that causes wheezing and Chronic cavitating Alveolar consolidation: lung infections Gram-positive cocci (S. pneumoniae) shortness of breath. Notably, asthma with abundant affects 250–300 million individuals of all acid-fast bacilli ages, races and ethnicities globally, and (M. tuberculosis) its prevalence is increasing alarmingly in the developing world21. Urbanization, with the loss of the microbial environment Bronchopneumonia Healthy from traditional rural lifestyles, strongly Inflammation in airways airway 22 and parenchyma: increases susceptibility to disease . Gram-negative rods Exacerbations are often triggered by viral (H. influenzae) infections23. Asthmatic airways typically Commensal contain considerable numbers of bacterial bacteria pathogens24–28 (FIG. 1) and may also carry as yet unexplored fungi. However, a causal link between these organisms and disease is yet to be established. Bronchiectasis Abnormal dilated airways full of The microbiota of healthy lungs secretions and Pulmonary infections with pathogens polymicrobial infections take place in the presence of commensal lower-airway microbial communities (the microbiota; reviewed in REF. 29). In brief, the sequencing of variable regions of the 16S Mucus rRNA gene has shown that healthy airways contain in the region of 100 operational taxonomic units (OTUs; as defined by Empyema Airway disease sequence similarity), which are dominated Infection in the Chronic dominance of pathogens by the Firmicutes (primarily Streptococcus pleural space: in asthmatic and COPD airways: spp. and Veillonella spp. OTUs) but also (S. pneumoniae Gram-negative Protebacteria and M. tuberculosis) (Haemophilus spp., Neisseria spp. contain Bacteroidetes (mostly Prevotella and Moraxella spp.) spp.), Fusobacteria, Actinobacteria and 10,24–28 Figure 1 | Pulmonary infections associated with bacterial pathogens. The airways and lung can Proteobacteria . Many of these OTUs may represent facultative anaerobes that are be affected in a number of different ways by bacterial infection, as shownNature clockwise Reviews | Microbiologystarting from the top right: lobar pneumonia affects a whole lobe of the lung and may spill into the surrounding recalcitrant to routine culture. The limited pleura (two thin layers of tissue that protect the lungs and allow them to move during breathing). number of phyla and the consistency of the Lobar pneumonia is typically caused by Gram-positive short chains of Streptococcus pneumoniae. oropharyngeal and lower-airway microbiota Bronchopneumonia is centred in the bronchial tree and spreads into adjoining lung tissues; it is most between multiple individuals and across commonly caused by the Gram-negative rods of Haemophilus influenzae. Asthma and chronic studies10,30–32 indicate that the airways are obstructive pulmonary disease (COPD) are diseases of the small airways, characterized by over- not simply passive recipients of inhaled growth of Proteobacteria (such as H. influenzae and Neisseria spp.) and the loss of normal commensal microbiota and provide strong evidence for species. Empyema is an infection of the pleural space and is most commonly caused by S. pneumo- host selection. These microbial communities niae. The chronic lung diseases bronchiectasis and cystic fibrosis are associated with chronic resist- 30 ant infections with abnormal bronchial morphology; these infections are caused by H. influenzae, are present in infants , and airways seem S. pneumoniae and opportunistic pathogens such as Staphylococcus aureus (a Gram-positive coccus) likely to be colonized in a way similar to and Pseudomonas aeruginosa (a Gram-negative flagellate bacillus). Mycobacterium tuberculosis other body surfaces33 during the weeks causes chronic consolidation

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